Environ Geochem Health DOI 10.1007/s10653-015-9681-4

ORIGINAL PAPER

The importance of iodine in public health John H. Lazarus

Received: 12 October 2014 / Accepted: 24 January 2015 Ó Springer Science+Business Media Dordrecht 2015

Abstract Iodine (I) deficiency has been known for more than a century and is known to cause cretinism at the extreme end of the spectrum but also, importantly, impaired development and neurocognition in areas of mild deficiency. The WHO has indicated that median urinary iodine of 100–199 lg/l in a population is regarded as indicative of an adequate iodine intake. The understanding of the spectrum of iodine deficiency disorders led to the formation of The International Council for the Control of Iodine Deficiency Disorders which has promulgated the use of household iodized salt and the use of such salt in food processing and manufacture. Iodine deficiency is particularly important in pregnancy as the fetus relies on maternal thyroxine (T4) exclusively during the first 14 weeks and also throughout gestation. As this hormone is critical to brain and nervous system maturation, low maternal T4 results in low child intelligence quotient. The recommendation for I intake in pregnancy is 250 lg/day to prevent fetal and child brain function impairment. During the past 25 years, the number of countries with I deficiency has reduced to 32; these still include many European developed countries. Sustainability of adequate iodine status must be

J. H. Lazarus (&) Thyroid Research Group, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff University, Cardiff, UK e-mail: [email protected]

achieved by continuous monitoring and where this has not been performed I deficiency has often recurred. More randomized controlled trials of iodine supplementation in pregnancy are required in mild iodinedeficient areas to inform public health strategy and subsequent government action on suitable provision of iodine to the population at risk. Keywords Iodine
Deficiency
Brain
Europe
Control
Thyroid
Child

Introduction The element iodine, a member of the seventh periodic group of elements, was discovered in 1811 by Courtois. It was not thought to be relevant to thyroid physiology until 1895 when its presence in the thyroid gland was first recognized. Marine (1915) found that thyroid tissue from dogs who were fed iodine contained a large amount of the element, especially if the dog was goitrous. During the twentieth century, following the introduction of radioisotopes and techniques of chemical analysis, the physiological role has been extensively investigated. This paper will focus on the effects of iodine deficiency in relation to maternal thyroid function and childhood brain development and cognitive outcomes. Iodine is an essential element for normal growth and development in animals and man. The healthy

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human contains 15–20 mg of iodine of which 70–80 % is in the thyroid gland. The normal daily requirement for dietary intake is 100–150 lg of iodine, but this requirement is increased in pregnancy to at least 200 lg/day. Following dietary ingestion, iodine is absorbed mainly in the jejunum and circulates in the plasma as inorganic iodine. The thyroid gland may be regarded as a factory utilizing iodine in the manufacture of thyroid hormones (Miot et al. 2014) (Fig. 1). Iodide is actively concentrated by the thyroid to 20–40 times compared to the plasma concentration. The mechanism of the concentrating process (sometimes known as the iodide trap) is through an iodide symporter situated on the basolateral membrane of the follicular cell. The symporter gene was cloned in 1996 (see Portulano et al. 2014), but more recently other iodide transporters have been described in the apical follicular membrane which transport the anion into the follicular lumen thus making it available for incorporation into tetraiodothyronine, i.e., thyroxine (T4) (Bizhanova and Kopp 2009). This process occurs on thyroglobulin, a 660 kD protein situated in the thyroid follicular lumen whose structure may be adversely affected by alterations in iodine status.

Fig. 1 Overview of the metabolism of iodine. Plasma iodide is derived from absorption from the gastrointestinal tract and concentrated by the thyroid gland. It is then incorporated into thyroid hormones, which circulate in the plasma. Plasma thyroid hormones are metabolised by the liver and excreted in the faeces; iodie is excreted in the urine

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The iodide cycle Ingested iodide is trapped in the thyroid, oxidized and bound to tyrosine to form iodotyrosines in thyroglobulin (TG); coupling of iodotyrosyl residues forms T4 and T3. Hormone secreted by the gland is transported in serum. Some T4 is deiodinated to T3. The hormone exerts its metabolic effect on the cell and is ultimately deiodinated; the iodide is reused or excreted in the kidney. A second cycle goes on inside the thyroid gland, with deiodination of iodotyrosines generating iodide, some of which is reused without leaving the thyroid. (From Miot et al., Thyroid disease manager 2012 accessed September 2014.) Once synthesized, T4 can enter the follicular cell thereby reaching the peripheral circulation when required. T4 is essentially a prohormone which is peripherally converted to triiodothyronine (T3) by deiodinase enzymes. This deiodination is noted in many tissues such as heart, kidney, liver and, importantly, the brain (Wirth et al. 2014). As will be discussed later, T4 is critically important for fetal central nervous system development and maturation and there is strong evidence for placental transfer of maternal T4 into the fetus.

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Geology Most iodine is found in the oceans. It is believed that large amounts of the element have been leached from the surface soil by glaciation, snow and rain resulting in carriage to the sea by rivers, floods and wind. Older soils and those at high altitude are more likely to be iodine deplete. Iodine occurs in the soil and sea as iodide. Iodide ions are oxidized to the volatile elemental iodine resulting in evaporation from the sea to the air. Iodine is subsequently returned to the soil although in lesser quantities so leading to iodine deficiency in the soil. It should be noted that this traditional view of the iodine cycle has been challenged by recent geochemical studies which broadly indicate the presence of complex molecules in seawater which bind iodine. There are also inconsistencies in iodine concentrations between iodine-deficient populations and the soil (sampled by soil bores) on which they live. The 1993 World Health Organisation (WHO) report on iodine deficiency disorders (IDDs) noted that ‘soil and inland bodies of water may become deficient of iodine due to the leaching effects of glaciation, snow, high rainfall and floods.’ Some of these assertions have been questioned as to their accuracy by environmental scientists who have indicated that environmental levels have not been measured (Maberly et al. 1981; Fuge and Johnson 1986). For example, the disorders of IDD have few or no borders in common with glaciation as determined from a comprehensive global survey (Kelly and Snedden 1958). The concentration and organification of iodine by algae occur in localized hot spots around the world’s oceans (Moore and Tokarczyk 1992). These compounds are released into the atmosphere, possibly by volatilization but more likely under biological control. There is a seasonal variation of atmospheric iodine, in association with the growth of marine algae. Iodine has been found in the atmosphere wherever it has been sought. This indicates that, although concentration decreases above the mean boundary layer (the line of separation above the surface-influenced atmosphere), iodine is transported easily around the globe. Once in the atmosphere, organic iodine in the gaseous phase interacts with ozone and other compounds in a complex of reactions. Indeed, iodine is more reactive than chlorine in ozone degradation. These reactions

determine the transit time in the atmosphere of iodine since different compounds have different weights and accordingly different depositional velocities due to gravity. Furthermore, it is likely that it is wet deposition [in rain and snow], not dry deposition by gravity, that controls the amount of iodine delivered to the surface of the earth. There is a direct relationship between rainfall and depositional amounts of iodine (Truesdale and Jones 1996). First, rain contains more iodine than later rain in the same shower, indicating some form of cleansing from the atmosphere of iodine in gas and dust. Atmospheric input of iodine to the soil is more important than any input resulting from the degradation of the underlying rock although it is not clear how the presumed initial high soil iodine came about or why it has changed. Iodine distribution in soils is governed both by the supply of iodine and by the ability of the soil to retain it (Fuge and Johnson 1986). Leaching of soil iodine is also unlikely since it is remarkably resistant to removal by water, whether hot or cold. The relationship between soil and plant concentrations of iodine is not a straightforward one (Whitehead 1979). Plants reject the large iodine ion by methylation and release into the local air where it is moved and re-deposited. Fuge suggests that this is the main mechanism for transporting iodine long distances inland (Fuge 1996) despite evidence of iodine even in polar air. Due to the presence of seaweed in coastal areas, there are some data suggesting a higher iodine status in populations living in coastal areas than those residing inland. This is not universal, and the reasons are more than just the volatility of iodine release from seaweed. It would seem probable that if environmental iodine is related to the incidence of IDD, then there would be a relationship between the distribution of IDD on the one hand and the atmospheric deposition and the distribution across the earth’s surface of iodine on the other hand.

Iodine deficiency Thyroidal adaptation to iodine deficiency The thyroidal response to iodine deficiency involves adjustment of all the physiological processes of thyroid hormone production to maximize the iodine use (Ingbar 1985). The thyroid enlarges in response to

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iodine deficiency, and large goiters may occur. The iodide-concentrating mechanism is stimulated resulting in an increased thyroidal iodine uptake. Although thyroid-stimulating hormone (TSH) is primarily responsible for thyroidal iodine uptake, plasma concentration of TSH is often not elevated suggesting a degree of thyroid autoregulation in this situation. There is a significantly increased thyroidal production of T3 as opposed to T4 as the former requires less iodine and is the biologically active circulating thyroid hormone in terms of action in peripheral tissues. In addition, there is very little iodine stored in thyroglobulin in the state of iodine deficiency compared to the iodine-sufficient state when thyroglobulin acts as a significant storage molecule for iodine. There is also an increased thyroidal iodine turnover in iodine deficiency. Epidemiology of iodine deficiency Iodine status is most accurately assessed in the population by measurement of urinary iodine concentration (UIC) in a random sample of urine in at least 40 individuals. This measurement will not indicate the iodine status of any one person but will show the adequacy of iodine nutrition and recent iodine intake in the population studied. The criteria for establishing iodine nutrition are shown in Table 1 and represent the conclusions of a WHO working group convened in 2005 (Public Health Nutrition 2007). It has been suggested that reliance on the proportion of UICs below 100 lg/L may overestimate the true prevalence of iodine deficiency (Zimmermann and Andersson 2012a). A new approach has been proposed

in which UIC survey data adjusted for intraindividual variation are extrapolated to iodine intakes and then interpreted using the estimated average requirement cut point model. This may more accurately define the prevalence iodine deficiency in a specific population. During the decade of 1980–1990, it was realized that the effects of iodine deficiency were apparent at the individual, social and national level (Hetzel 2012). The term iodine deficiency disorders was introducted to indicate the various effects of iodine deficiency on growth and development. It was also apparent that this condition was serious enough to threaten the social and economic development of many developing countries as well as still being observed to a lesser degree in areas such as Europe. To help address this problem, The International Council for the Control of Iodine Deficiency Disorders (ICCIDDs) was formed in 1986. This is now ICCIDD Global Network (www. iccidd.org) and in 2014 has now been named simply Iodine Global Network. This non-governmental organization sets out to collaborate with WHO and United Nations Children’s Fund (UNICEF) to develop national IDD control programs in countries with significant IDD problems. A major function of ICCIDD was and still is to communicate the IDD message and awareness to national governments, decision makers, international agencies as well as all relevant health professionals and planners. IDD has operated by organizing meetings and contributing to seminars and workshops in all continents. It is important to note that membership of ICCIDD is all inclusive and not just confined to medical personnel. In addition to endocrinologists and public health workers membership includes salt producers, management specialists,

Table 1 From WHO/UNICEF/ICCIDD Median urinary iodine (lg/L)

Iodine intake

Iodine nutrition

\20

Insufficient

Severe iodine deficiency

20–49

Insufficient

Moderate iodine deficiency

50–99

Insufficient

Mild iodine deficiency

100–199

Adequate

Optimal

200–299

More than adequate

Risk of iodine-induced hyperthyroidism within 5–10 years following introduction of iodized salt in susceptible cases

[300

Excessive

Risk of adverse health consequences (iodine-induced hyperthyroidism, autoimmune thyroid disease

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communicators, laboratory analysts, researchers and others. Universal salt iodization, in which all salt used in agriculture, food processing, catering and household should be iodized, is the agreed strategy for achieving iodine sufficiency. During the last 25 years or so, great progress has been made toward the goal of elimination of worldwide IDD (Hetzel 2012). However, IDD is still a major public health problem worldwide and WHO estimates that 740 million people are currently affected by goiter (Fig. 2). The mobilization of WHO, UNICEF and ICCIDD has resulted in remarkable progress in IDD control, especially in Africa and in Southeast Asia where the endemia was the most severe. However, 32 countries are still iodine deficient and 44 % of school-aged children in Europe still have insufficient iodine intake (Zimmermann and Andersson 2012a, b). West and Central Europe has a total population of about 600 million situated in 35 countries with a country population ranging from 0.3 to 75 million. Attention was drawn to the iodine deficiency problem in this area more than 10 years ago (Delange 2002). In general, the iodine deficiency is mild, but nevertheless this may impact on childhood development. For example, mildmoderate iodine deficiency in the first trimester of pregnancy was associated with increased odds of

offspring intelligence quotient (IQ) being in the lowest quartile (OR 1.43 95 % CI 1.04, 1.98, p = 0.03) with the greatest negative impact observed with verbal IQ (OR 1.66, 95 % CI 1.20, 2.31, p = 0.002) (Bath et al. 2013). Review of the current evidence indicates that correction of mild-to-moderate iodine deficiency improves cognitive performance in school-age children, but there is insufficient data on developmental outcomes in early life (Taylor et al. 2013). There are two randomized studies of iodine supplementation in children with mild iodine deficiency in Albania (Zimmermann et al. 2006) and New Zealand (Gordon et al. 2009) showing improved cognition. However, large-scale controlled trials are now needed to clarify whether gestational iodine supplementation will benefit infant and childhood neurodevelopment in more European countries with marginal iodine deficiency. Thyroid physiology in pregnancy and thyroid function tests Pregnancy has an appreciable effect on thyroid economy (Glinoer 1997; Krassas and Poppe 2010). There is an increased excretion of iodine in the urine accounting for the increase in thyroid volume in areas of moderate and severe deficiency but not in iodine-

Fig. 2 Iodine status in the World 2012. Adapted from Zimmermann and Andersson (2012b)

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sufficient regions. Iodine deficiency during pregnancy is associated with maternal goiter and reduced maternal thyroxine (T4) level, which is seen in areas of endemic cretinism (Lazarus and Smyth 2009). The iodine requirements during gestation were considered by a WHO Technical Consultation in 2005. The recommendations are shown in Table 2 for pregnant women, lactating women and children less than 2 years old. It is apparent that the requirements in pregnancy are substantially greater than the non-pregnant state, corresponding to a urinary iodine concentration of 150–249 lg/L being regarded as adequate (Andersson et al. 2007). Thyroid hormone transport proteins particularly thyroxine-binding globulin (TBG) increase due to enhanced hepatic synthesis and a reduced degradation rate due to oligosaccharide modification. Serum concentration of thyroid hormones has been reported to be decreased, increased or unchanged during gestation by different groups depending on the assays used. Assays employing total thyroxine (TT4) show a result approximately 1.5 times the non-pregnant value. There is general consensus that there is a transient rise in free thyroxine (FT4) in the first trimester due to the relatively high circulating human chorionic gonadotropin (hCG) concentration and a decrease of FT4 in the second and third trimester albeit within the normal reference range (Brent 1997). Changes in free triiodothyronine (FT3) concentration are also seen in which they broadly parallel the FT4, again within the normal range. The precise reason for the decline in free thyroid hormones is not clear, but the interaction of thyroid-stimulating hormone (TSH), estrogen and thyroid-binding proteins is of importance (Glinoer 1997). In iodine-deficient

areas, hypothyroxinemia with preferential T3 secretion may occur accompanied by a rise in median TSH and serum thyroglobulin. Thyroidal stimulation by hCG in severely iodine-deficient areas leads to preferential T3 secretion which results in lowered serum T4, i.e., hypothyroxinemia. It is probable that the changes in thyroid hormone during gestation relate to the necessity of delivering thyroxine to the fetal cells, particularly neuronal cells. Adequate concentrations of T4 are essential for neural development, and this T4 can only be maternally derived from, at least during the first trimester. Adequate iodine nutrition is essential so as to allow for maternal (and later in gestation) fetal T4 synthesis. The placenta plays an important role in T4 and iodide transport, although details are still unclear (Chan et al. 2009; Burns and O’Herlihy 2011; Burns et al. 2011). The placenta secretes hCG, a glycoprotein hormone sharing a common alpha subunit with TSH but having a unique beta subunit, which confers specificity. hCG, or a molecular variant, acts as a TSH agonist, so that elevated levels contribute to the cause of gestational transient hyperthyroxinemia seen in about 0.3 % of pregnancies. Hyperemesis gravidarum, which sometimes requires hospitalization because of the development of dehydration and ketosis, may be associated with hyperthyroidism due to excess hCG stimulation, and hyperthyroidism is also seen in some cases of hydatidiform mole where excess hCG is secreted. Iodine and the developing nervous system Thyroid hormones are major factors for the normal development of the brain. The mechanisms of actions of thyroid hormones in the developing brain are mainly mediated through two ligand-activated thyroid hormone receptor isoforms. It is known that thyroid

Table 2 Daily recommended nutrient intake (RNI) for iodine proposed for pregnant and lactating women, and children less than 2 years old, and the daily intake that is considered should not be exceeded Population group

Recommended iodine intake (lg day-1)

Level of iodine intake beyond which no added health benefit can be expected (lg day-1)

Pregnant women

250

[500

Lactating women

250

[500

90

[180

Children less than 2 years old

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hormone deficiency may cause severe neurological disorders resulting from the deficit of neuronal cell differentiation and migration, axonal and dendritic outgrowth, myelin formation and synaptogenesis. This is the situation well documented in iodine-deficient areas where the maternal circulating thyroxine concentrations are too low to provide adequate fetal levels particularly in the first trimester. There is also evidence that in an iodine-sufficient area maternal thyroid dysfunction (hypothyroidism, subclinical hypothyroidism or hypothyroxinemia) during pregnancy results in neurointellectual impairment of the child. During the early twentieth century, it was noted that studies of endemic cretinism had suggested that the fetal developing thyroid was dependent on factors that may impair the maternal thyroid reserve (Hetzel 1983). Subsequently, a cause–effect relationship was shown between maternal iodine deficiency and the birth of neurological cretins. Furthermore, there was evidence that the degree of maternal hypothyroxinemia correlated with the CNS damage of the progeny. These data were difficult to explain at the time due to the fact that it was not thought that transplacental thyroid hormone transport took place. The view was that the placenta was impermeable to iodothyronines and that small amounts possibly transferred would be of no physiological importance. It has now been shown convincingly that this does indeed occur not only before the fetal thyroid starts to synthesize thyroid hormones (i.e., up to 12- to 14-week gestation) but right through pregnancy (Vulsma et al. 1989). Although fetal thyroid function does not commence until the equivalent of 12-week gestation in man, the presence of functional fetal nuclear receptors for T3 is noted in early pregnancy indicating that triiodothyronine is exerting an action at this time (De Nayer and Dozin 1989). Maternal thyroid hormone is necessary before onset of fetal thyroid function as shown by interference of cortical cell migration and the cortical expression of several genes in the fetuses of mothers rendered hypothyroid by goitrogens. After fetal thyroid function is present, maternal thyroxine still contributes to the thyroid hormone available to the fetal tissues at term. Indeed, the maternal T4 is sufficient to prevent fetal cerebral T3 deficiency until birth in a hypothyroid fetus. The T3 at this stage is locally produced in cerebral structures by deiodination of T4 by the type 2 iodothyronine deiodinase, hence

the requirement for T4. Both the type 2(D2) and type 3(D3) deiodinases are critical in producing and modulating the supply of T4 to the fetus as well as producing locally derived T3. The type 3 enzyme is mainly placentally located and inactivates T4 and T3 thereby regulating the influx of T4 to the fetus (Chan et al. 2009). Corroborative data have been obtained by extensive studies of iodine deficiency in sheep (Hetzel and Mano 1994). In these animals, induced iodine deficiency results in reduced brain weight, a reduction in brain DNA and retarded myelination. In keeping with earlier observations, morphological changes in the cerebellum were noted accompanied by delayed maturation (Hetzel et al. 1989). The complexity of the effect of thyroid hormone on brain development is illustrated in Fig. 3 which illustrates thyroid hormone supply to the fetus and the development of different brain structures at different stages of gestation and postnatal life (Williams 2008). Iodine deficiency and neurocognition of the offspring Although iodine deficiency is still present in many parts of the world including Europe, it is usually mild to moderate in degree. Nevertheless, this has significant adverse effects on brain development and this was shown by a reduction in psychointellectual development in 3-year-old Spanish children born to mothers whose urinary iodine concentrations were less that 100 lg/L at 12-week gestation (Velasco et al. 2009). Of importance is a non-randomized observation that children whose mothers had received an iodine supplement of 300 lg per day during the first trimester of pregnancy had higher scores on the Psychomotor Developmental Index and Behaviour Rating Scale than children from women who had received no iodine supplements (Galan et al. 2005). The children receiving iodine were studied at 5.5 months, whereas the control group was studied at 12.4 months so that the results were regarded as preliminary. Because the maternal T4 concentration is one important factor related to delayed neurobehavioral development, Berbel et al. (2009) evaluated the effect of iodine supplementation on neurocognitive performance in 18-month-old children from mothers who were hypothyroxinemic in gestation with or without iodine supplements. The study showed that a

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Fig. 3 Relationship between thyroid hormone action and development of the brain. In the first trimester of pregnancy, early neuronal proliferation and migration are dependent on maternal thyroxine (T4). From Williams (2008)

delay of 6–10 weeks in iodine supplementation of hypothyroxinemic mothers in early gestation increased the risk of neurodevelopmental delay in the progeny. Previous studies of iodine supplementation in pregnancy between 1991 and 2002 had not evaluated child neurocognitive function but had demonstrated amelioration of features of iodine deficiency in the mothers. Even in an iodine-sufficient area, maternal thyroid dysfunction (hypothyroidism, subclinical hypothyroidism or hypothyroxinemia) during pregnancy results in neurointellectual impairment of the child; hence, maternal thyroid hormones are required through gestation for proper brain development and

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specific effects will depend on when maternal hormone deficiency occurs during pregnancy (Rovet and Willoughby 2010). Man et al. (1991) first reported impaired childhood cognitive function in children born to mothers with low thyroid function in pregnancy and also noted prevention of this impairment in a small study by maternal treatment with levothyroxine. Low maternal thyroid hormone concentrations in early gestation can be associated with significant decrements of IQ of young children (see Lazarus 2011), and also a significant decrement in IQ is observed in children born to euthyroid mothers with circulating anti-TPO antibodies (Lazarus 2011). Haddow et al. (1999) found in a retrospective study that the

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full IQ scores of children whose mothers had a high TSH during gestation were 7 points lower than controls (p \ 0.005) and that 19 % of them had scores of less than 85 compared to 5 % of controls (p \ 0.007). Reduction in IQ has been reported in the children of mothers with FT4 in the lowest tenth decile in the first trimester (Lazarus 2011). A Chinese study (Li et al. 2012) has confirmed that children aged between 25 and 30 months whose mothers were noted to have increased maternal TSH, decreased serum T4 and even elevated TPO antibodies had lower intelligence scores and lower motor scores than those children born to euthyroid mothers. A prospective study in the same country (Su et al. 2011) showed that maternal subclinical hypothyroidism diagnosed up to 20-week gestation resulted in neurodevelopmental delay in the infants. The Generation R Study, a population-based cohort study (Henrichs et al. 2010), showed no relation of cognitive outcome with maternal TSH but a significantly higher risk of expressive language delay in children from mothers with mild and severe hypothyroxinemia. A further study by the same group indicated that thyroid function is crucial for fetal brain development, which determines problem behavior later in life (Ghassabian et al. 2011). A study has also shown that offspring of mothers with hypothyroxinemia in early pregnancy(aged 5 years) performed less well than children of normothyroxinemic mothers in a simple reaction time test that involved minimal cognitive function (Martijn et al. 2013). Other recent data have not confirmed decrements in cognitive function in relation to thyroid dysfunction in gestation. For example, in a historical cohort study in Iran, the IQ level and cognitive performance of children born to L-T4-treated hypothyroid mothers were similar to those whose mothers had untreated subclinical hypothyroidism in pregnancy and to those whose mothers had normal thyroid function (Behrooz et al. 2011). In an observational nested case–control study, isolated hypothyroxinemia in the second trimester was not associated with impaired infant development assessed at age 2 years (Craig et al. 2012). It has also been reported that IQ and DQ (development quotient) scores indicated no apparent neurodevelopmental deficit in children whose mothers had overt hypothyroidism during the first trimester of pregnancy and were restored to normal serum T4 levels by late pregnancy (Downing et al. 2012). On the other hand, evaluation of preterm

infants has shown that exposure to hypothyroxinemia may be important for neurodevelopment with a decrease being found up to 5.5 years of age (Delahunty et al. 2010). During 2013, a postal enquiry survey was performed requesting relevant information on iodine status from all national coordinators of ICCIDD GN in the region. Information from all countries was not available for some items of the questionnaire. In pregnancy, the median UI should be at least 150 lg/L on account of increased I requirements during gestation and lactation (Lazarus and Smyth 2009). The results of the questionnaire (Lazarus 2014) showed firstly that mandatory salt iodization is available in 13 out of 21 countries. This represents at least 400 million people living in countries with no mandatory legislation for iodized salt. No data are available from this survey on the household iodized salt coverage rates. Some countries such as Switzerland have a high rate (80 %) but in others (e.g., UK) coverage is only about 5 %. Median urinary iodine (UI) concentration either national or regional ranged from 78 to 252 lg/L in 26 countries with 6 of those countries (23 %) having UI \100 lg/L. Data on I status in pregnancy were available from 21 countries and indicated that this was adequate in only 8 (38 %). When asked as to whether there is ongoing monitoring of iodine status in the country 16 national coordinators responded positively, but 17 indicated that there was no monitoring. A few country examples will illustrate the situation further. In the Netherlands, iodine intake in pregnant women is sufficient as determined by a single urinary iodine measurement in [1,000 pregnant women in Rotterdam with a median UI of 225 lg/L (Medici et al. 2014). This is in contrast to Norway where the median UI was \100 lg/L in an admittedly smaller sample (Brantsaeter et al. 2013). In Poland, there has been an improvement in median UI in pregnancy from 2010 (105 lg/L) to 121 lg/L in 2011, but this figure is still suboptimal (Szybinski 2012). A comprehensive evaluation of iodine status in pregnancy in Belgium has shown that median UI values are suboptimal (Moreno-Reyes et al. 2013). This is despite the fact that 60 % of women reported taking iodine supplements during gestation (Vandevijvere et al. 2013). Interestingly, the frequency of elevated neonatal TSH was still low (3 %) in this population (Vandevijvere et al. 2012). In Denmark, while the majority of

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pregnant women took iodine-containing supplements, the subgroup of non-users was still iodine-deficient after the introduction of iodine fortification of salt (Andersen et al. 2013). The iodine status is adequate in some countries. Following a new salt law in Croatia (population 4.5 m) in 1996, UI values have steadily increased from \100 lg/L in 1997 to 150 in 2002 and even higher (approx. 200) in 2009 (Kusic´ et al. 2009). This is a success story in a small country but also shows the necessity of further monitoring, in this case to avoid iodine excess. In Kosovo and Montenegro in 2007, there was optimum iodine nutrition (van der Haar et al. 2011) and this is continuing in the former but not in Montenegro because of lack of funding. In Romania (population 19 m) subsequent to mandatory iodization in 2002/3, UI has increased from approximately 90 lg/L in 2004 to 135 lg/L in 2011, a satisfactory outcome. However, there is suboptimal iodine status in pregnant women in nine countries (Albania, Belgium, Czech Republic, Greece, Israel, Norway, Portugal, Romania, Serbia) and evidence of iodine deficiency in the general as well as the pregnant population in five countries (France, Hungary, Ireland, Italy and UK). This means that an inadequate iodine supply in pregnancy is present in approximately 30 % of European countries. The most populous countries in the region are France, Germany, Italy, Spain, Turkey and UK with a combined population of about 390 m, that is, 2/3 of the whole area. Only two of these countries (Italy and Spain) have iodization legislation which is not always adhered to. In contrast, all but two of the countries (Spain and UK) have national monitoring. There have been several regional studies in Spain, for example, in Catalonia (Vila et al. 2011). The UI in the general population is adequate in Spain (although deficient in N Spain (Aguayo et al. 2013) and France but borderline or mildly deficient in the others. Moderate to severe ID still existed in 2007 in 27.8 % of the Turkish population, which was much better compared to 1997 and 2002 (Erdogan et al. 2009). In the UK, iodine deficiency has emerged as a public health issue following several decades of apparent iodine sufficiency (Phillips 1997). There is evidence of iodine deficiency from a national survey of 15-year-old schoolgirls (Vanderpump et al. 2011) as well as in pregnant women from several areas (Bath et al. 2008; Pearce et al. 2010). A longitudinal study of

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children from pregnancy to age 20 has shown significant associations between suboptimal maternal iodine nutrition and intellectual performance (Bath et al. 2013). There is a requirement for a national large-scale survey of iodine supply in pregnant women in UK to confirm the initial findings in relatively small samples. There are some indications that UIC in young UK schoolchildren is adequate (Rayman personal communication). However, this group usually consume the largest amount of milk and their I status cannot be used as proxy for the adult population (Pearce et al. 2013). In summary, there is re-emerging iodine deficiency in industrialized countries of Europe although the iodine status of some countries is satisfactory. Of particular concern is the fact that many countries have inadequate iodine nutrition in their pregnant women. It also appears that about 400 m people from 20 countries have no or limited access to iodized salt. The demonstration of adequate iodine intake in some sections of the population (e.g., schoolchildren) should not be a barrier to recommending a national salt iodization program. Thus, the overall picture of iodine nutrition in Europe in the early twenty-first century is still a cause for concern (with some exceptions). Salt iodization is known to be a highly cost-effective method of supplying iodine to a population although there are other sources of iodine that can be employed. ICCIDD GN has an admirable record in advocacy during the past nearly 30 years in relation to promotion of universal salt iodization and increasing awareness of iodine deficiency and its adverse consequences particularly in children. As indicated above, a significant population in Europe is mildly deficient in iodine; an increase in dietary iodine consumption by 50–100 mcg/day would be beneficial with minimal or no adverse consequences. More national data are required, particularly in the pregnant population where current evidence, although incomplete for many countries, suggests that there is suboptimal iodine nutrition in this population. The evidence presented does point to a significant effect of gestational maternal thyroid dysfunction (high TSH only, hypothyroxinemia or overt hypothyroidism) on neonatal and child neurodevelopment. However, the strength of the evidence is variable due to such factors as the type of study, the numbers of subjects studied, the age at which psychological evaluation was performed as

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well as the specific tests employed together with other unknown factors. There are few prospective studies. A report from Moscow in a small number of subjects (Kasatkina et al. 2006) found that early (not later than 9-week gestation) administration of thyroxine 1.2 lg/kg to women with gestational hypothyroxinemia improved neurointellectual performance of the children during the first year. The Controlled Antenatal Thyroid Screening Study (CATS) (Lazarus et al. 2012) was a prospective randomized double-blind study adequately powered in which a large number of children (390 in the screen group and 404 in the control group) were evaluated at 3 years of age. Mothers of screen group children (from mildly iodine-deficient areas) had received 150 lg T4 from before 14-week gestation, while mothers of control group children had not received T4 therapy. The antenatal screening for thyroid function at a median of 12 weeks and 3 days and maternal treatment for hypothyroidism did not result in improved cognitive function in the children at 3 years. The discrepancy between this finding and those of previous studies may be due to the lateness of screening, the modest median TSH in the screen group and the fact that more specific cognitive impairments (such as expressive language delay, vision abnormalities and behavioral changes) were not specifically tested. Despite the negative results from the CATS study the momentum directed at prenatal or early gestational thyroid function screening with thyroid hormone intervention continues to increase. The cost-effectiveness of no screening versus routine screening for subclinical hypothyroidism in pregnancy had demonstrated a saving of approximately $8.3 million per 100,000 women screened. A recent report also showed screening to be cost-effective in various clinical scenarios, including that of untreated maternal hypothyroidism resulting in decreased child intelligence, with levothyroxine therapy being preventive (Dosiou et al. 2012). There is abundant observational evidence from animal and human studies that thyroid hormone has an important influence on cognitive function especially in childhood but also in preterm infants and the elderly. While the recent randomized prospective study has failed to show benefit of maternal thyroxine treatment on cognitive function, more trials are required to

confirm these findings perhaps employing more specific psychological tests. We now require to move forward in Europe by increasing advocacy activities, providing more epidemiological evidence as well as involving the European Union to recognize and prevent the problems of iodine deficiency in its backyard. This review has emphasized the importance of iodine deficiency in relation to the developing brain. It is noted that even mild deficiency can result in impaired childhood neurocognition. ICCIDD was formed to combat the spectrum of iodine deficiency disorders in the world which are still one of the leading causes of mental impairment. A significant increase in our understanding of the physiology of thyroid function in pregnancy has underpinned the continued importance of the work of ICCIDD. While iodine deficiency has been reduced to just 32 countries in the world millions of school-age children are still at risk and continuous monitoring of iodine status is an essential public health measure. The future research agenda should include further studies of the neurobiology of thyroid hormone and central nervous system development and clinical trials of iodine supplementation in pregnancy, particularly in mildly deficient areas. Continuing advocacy to improve iodine status in deficient countries is recommended. The latter is not always easily achieved especially in developed countries, and several stakeholders are required in this situation. Much has been achieved, but there is more to do. Acknowledgments I thank the national coordinators of ICCIDD West and Central Europe for their help with the questionnaireConflict of interestJH Lazarus has no conflict of interest.

References Aguayo, A., Grau, G., Vela, A., Aniel-Quiroga, A., Espada, M., Martul, P., et al. (2013). Urinary iodine and thyroid function in a population of healthy pregnant women in the North of Spain. Journal of Trace Elements in Medicine and Biology, 27, 302–306. Andersen, S. L., Sorensen, L. K., Krejbjerg, A., Moller, M., & Laurberg, P. (2013). Iodine deficiency in Danish pregnant women. Danish Medical Journal, 60, A4657. Andersson, M., de Benoist, B., Delange, F., & Zupan, J. (2007). Prevention and control of iodine deficiency in pregnant and lactating women and in children less than 2-years-old:

123

Environ Geochem Health Conclusions and recommendations of the Technical Consultation. Public Health Nutr, 10, 1606–1611. Bath, S. C., Steer, C. D., Golding, J., Emmett, P., & Rayman, M. P. (2013). Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: Results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet, 382, 331–337. Bath, S., Walter, A., Taylor, A., & Rayman, M. P. (2008). Iodine status of UK women of childbearing age. Journal of Human Nutrition & Dietetics, 21, 379–380. Behrooz, H. G., Tohidi, M., Mehrabi, Y., Behrooz, E. G., Tehranidoost, M., & Azizi, F. (2011). Subclinical hypothyroidism in pregnancy: Intellectual development of offspring. Thyroid, 21, 1143–1147. Berbel, P., Mestre, J. L., Santamarı´a, A., Palazo´n, I., Franco, A., Graells, M., et al. (2009). Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: The importance of early iodine supplementation. Thyroid, 19, 511–519. Bizhanova, A., & Kopp, P. (2009). Minireview: The sodiumiodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology, 150(3), 1084–1090. Brantsaeter, A. L., Abel, M. H., Haugen, M., & Meltzer, H. M. (2013). Risk of suboptimal iodine intake in pregnant Norwegian women. Nutrients, 5, 424–440. Brent, G. A. (1997). Maternal thyroid function: interpretation of thyroid function tests in pregnancy. Clinical Obstetrics and Gynecology, 40, 3–15. Burns, R., O’Herlihy, C., & Smyth, P. P. (2011a). The placenta as a compensatory iodine storage organ. Thyroid, 2, 541–546. Burns, R., Azizi, F., Hedayati, M., Mirmiran, P., O’Herlihy, C., & Smyth, P. P. (2011b). Is placental iodine content related to dietary iodine intake? Clinical Endocrinology (Oxford), 75, 261–264. Chan, S. Y., Vasilopoulou, E., & Kilby, M. D. (2009). The role of the placenta in thyroid hormone delivery to the fetus. Nature Clinical Practice Endocrinology & Metabolism, 5, 45–54. Craig, W. Y., Allan, W. C., Kloza, E. M., Pulkkinen, A. J., Waisbren, S., Spratt, D. I., et al. (2012). Mid-gestational maternal free thyroxine concentration and offspring neurocognitive development at age two years. Journal of Clinical Endocrinology and Metabolism, 97, E22– E28. De Nayer, P., & Dozin, B. (1989). Thyroid hormone receptors in the developing brain. In G. R. Delong, J. Robbins, & P. G. Condliffe (Eds.), Iodine and the brain (pp. 51–58). New York: Plenum Press. Delahunty, C., Falconer, S., Hume, R., et al. (2010). Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcome at 5 1/2 years: Millennium cohort study. Journal of Clinical Endocrinology and Metabolism, 95, 4898–4908. Delange, F. (2002). Iodine deficiency in Europe and its consequences: An update. European Journal of Nuclear Medicine and Molecular Imaging, 29, S404–S416. Dosiou, C., Barnes, J., Schwartz, A., Negro, R., Crapo, L., & Stagnaro-Green, A. (2012). Cost-effectiveness of universal and risk-based screening for autoimmune thyroid disease in

123

pregnant women. Journal of Clinical Endocrinology and Metabolism, 97, 1536–1546. Downing, S. D., Halpern, L., Carswell, J., & Brown, R. S. (2012). Severe early maternal hypothyroidism corrected prior to the third trimester associated with normal cognitive outcome in the offspring. Thyroid, 22, 625–630. Erdog˘an, M. F., Ag˘baht, K., Altunsu, T., Ozbas¸ , S., Yucesan, F., Tezel, B., et al. (2009). Current iodine status in Turkey. Journal of Endocrinological Investigation, 32, 617–622. Fuge, R. (1996) Geochemistry of iodine in relation to iodine deficiency diseases. In J. D. Appleton, R. Fuge, G. J. H. McCall (Eds.), Environmental geochemistry and health (pp. 201–211). London: The Geological Society, Special Publication 113. Fuge, R., & Johnson, C. C. (1986). The geochemistry of iodine—A review. Environmental Geochemistry and Health, 8, 31–54. Galan, R. G., Martinez, P. S., Diaz, M. P. M., & Crespo, M. F. R. (2005). Psycho-intellectual development of 3 year old children with early gestational iodine deficiency. Journal of Pediatric Endocrinology and Metabolism, 18, 1265–1272. Ghassabian, A., Bongers-Schokking, J. J., Henrichs, J., Jaddoe, V. W., Visser, T. J., Visser, W., et al. (2011). Maternal thyroid function during pregnancy and behavioral problems in the offspring: The generation R study. Pediatric Research, 69, 454–459. Glinoer, D. (1997). The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocrine Reviews, 18, 404–433. doi:10. 1210/er.18.3.404. Gordon, R. C., Rose, M. C., Skeaff, S. A., Gray, A. R., Morgan, K. M., & Ruffman, T. (2009). Iodine supplementation improves cognition in mildly iodine-deficient children. American Journal of Clinical Nutrition, 90, 1264–1271. Haddow, J. E., Palomaki, G. E., Allan, W. C., Williams, J. R., Knight, G. J., Gagnon, J., et al. (1999). Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine, 341, 549–555. Henrichs, J., Bongers-Schokking, J. J., Schenk, J. J., Ghassabian, A., Schmidt, H. G., Visser, T. J., et al. (2010). Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: The generation R study. Journal of Clinical Endocrinology and Metabolism, 95, 4227–4234. Hetzel, B. S. (1983). Iodine deficiency disorders (IDD) and their eradication. Lancet, 2, 1126–1129. Hetzel, B. S. (2012). The development of a global program for the elimination of brain damage due to iodine deficiency. Asia Pacific Journal of Clinical Nutrition, 21, 164–170. Hetzel, B. S., & Mano, M. L. (1994). Hormone nurturing of the developing brain: Sheep and marmoset models. In J. B. Stanbury (Ed.), The damaged brain of iodine deficiency (pp. 123–130). New York: Cognizant Communication Corporation. Hetzel, B. S., Mano, M. L., & Chevadev, J. (1989). The fetus and iodine deficiency: Marmoset and sheep models of iodine deficiency. In G. R. Delong, J. Robbins, & P. G. Condliffe (Eds.), Iodine and the brain (pp. 177–186). New York: Plenum Press.

Environ Geochem Health Ingbar, S. H. (1985). Autoregulation of the thyroid: The effects of thyroid iodine enrichment and depletion. In R. Hall & J. Kobberling (Eds.), Thyroid disorders associated with iodine deficiency and excess (Vol. 22, pp. 153–161). New York: Raven Press. Kasatkina, E. P., Samsonova, L. N., Ivakhnenko, V. N., Ibragimova, G. V., Ryabykh, A. V., Naumenko, L. L., et al. (2006). Gestational hypothyroxinemia and cognitive function in offspring. Neuroscience and Behavioral Physiology, 36, 619–624. Kelly, F. C., & Snedden, W. W. (1958). Prevalence and geographical distribution of endemic goitre. Bulletin of the World Health Organisation, 18, 5–173. Krassas, G. E., & Poppe, K. (2010). Glinoer D thyroid function and human reproductive health. Endocrine Reviews, 31, 702–705. Kusic´, Z., Jukic´, T., Rogan, S. A., Juresa, V., Dabelic´, N., Stanicic´, J., et al. (2009). Current status of iodine intake in Croatia: the results of 2009 survey. Collegium Antropologicum, 2012(36), 123–128. Lazarus, J. H. (2011). Thyroid function in pregnancy. British Medical Bulletin, 97, 137–148. Lazarus, J. H. (2014). Iodine status in Europe in 2014. European Thyroid Journal, 3, 3–6. Lazarus, J. H., Bestwick, J. P., Channon, S., Channon, S., Paradice, R., Maina, A., et al. (2012). Antenatal hypothyroid screening and childhood cognitive function. New England Journal Medicine, 366, 493–501. Lazarus, J. H., & Smyth, P. P. A. (2009). Iodine deficiency in pregnancy: Iodine deficiency and supplementation in pregnancy. In V. R. Preedy, G. N. Burrow, & R. Watson (Eds.), Comprehensive handbook of iodine: Nutritional, biochemical, pathological and therapeutic aspects (pp. 469–476). Oxford: Academic. Li, Y., Shan, Z., Teng, W., Yu, X., Li, Y., Fan, C., et al. (2012). Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clinical Endocrinology, 72, 825–829. Maberly, G. F., Eastman, C. F., & Corcoran, J. M. (1981). Effect of iodination of a village water supply on goitre size and thyroid function. Lancet, 2, 1270–1272. Man, E. B., Brown, J. F., & Serunian, S. A. (1991). Maternal hypothyroxinemia: psychoneurological deficits of progeny. Annals of Clinical and Laboratory Science, 21, 227–239. Marine, D. (1915). Quantitative studies on the in vivo absorption of iodine by dogs’ thyroid glands. Journal of Biological Chemistry, 22, 547–550. Martijn, J. J., Finken, M. J. J., van Eijsden, M., Eva, M., Loomans, E. M., Vrijkotte, T. G. M., et al. (2013). Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. Journal of Clinical Endocrinology and Metabolism, 98, 1417–1426. Medici, M., Ghassabian, A., Visser, W., de Muinck KeizerSchrama, S. M., Jaddoe, V. W., Visser, W. E., et al. (2014). Women with high early pregnancy urinary iodine levels have an increased risk of hyperthyroid newborns: the population-based Generation R Study. Clinical Endocrinology, 80, 598–606.

Miot, F., Dupuy, C., Dumont, J., & Rousset, B. (2014). Thyroid hormone synthesis and secretion in Thyroid Disease Manager. http://www.thyroidmanager.org. Accessed September 2014. Moore, R. M., & Tokarczyk, R. (1992). Chloro-iodomethane in North Atlantic Waters: A potentially significant source of atmospheric iodine. Geophysical Research Letters, 19, 1779–1782. Moreno-Reyes, R., Glinoer, D., Van Oyen, H., & Vandevijvere, S. (2013). High prevalence of thyroid disorders in pregnant women in a mildly iodine-deficient country: A populationbased study. Journal of Clinical Endocrinology and Metabolism, 98, 3694–3701. Pearce, E. N., Andersson, M., & Zimmermann, M. B. (2013). Global iodine nutrition: Where do we stand in 2013? Thyroid, 23, 523–528. Pearce, E. N., Lazarus, J. H., Smyth, P. P., He, X., Dall’amico, D., Parkes, A. B., et al. (2010). Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women. Journal of Clinical Endocrinology and Metabolism, 95, 3207–3215. Phillips, D. I. (1997). Iodine, milk, and the elimination of endemic goitre in Britain: The story of an accidental public health triumph. Journal of Epidemiology and Community Health, 51, 391–393. Portulano, C., Paroder-Belenitsky, M., & Carrasco, N. (2014). The Na?/I- symporter (NIS): Mechanism and medical impact. Endocrine Reviews, 35(1), 106–149. Public Health Nutrition (2007). 10;12(A) Special Issue. Report of a WHO Technical Consultation on prevention and control of iodine deficiency in pregnancy, lactation and in children less than 2 years of age. In B. de Benoist, F. Delange (Eds.). Rovet, J. F., & Willoughby, K. A. (2010). Maternal thyroid function during pregnancy: Effects on the developing fetal brain. In A. W. Zimmermann & S. L. Connors (Eds.), Maternal influences on fetal neurodevelopment: Clinical and research aspects (pp. 55–77). New York: Springer Science?Business Media. Su, P. Y., Huang, K., Hao, J. H., Xu, Y. Q., Yan, S. Q., Li, T., et al. (2011). Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: A prospective population-based cohort study in China. Journal of Clinical Endocrinology and Metabolism, 96, 3234–3241. Szybin´ski, Z. (2012). Work of the Polish council for control of iodine deficiency disorders, and the model of iodine prophylaxis in Poland. Endokrynologia Polska, 63, 156–160. Taylor, P. N., Okosieme, O. E., Dayan, C. M., & Lazarus, J. H. (2013). Impact of iodine supplementation in mild-tomoderate iodine deficiency: Systematic review and metaanalysis. European Journal of Endocrinology, 19(170), R1–R5. Truesdale, V. W., & Jones, S. D. (1996). The variation of iodate and total iodine in some UK rainwaters during 1980–1981. Journal of Hydrology, 179, 67–86. van der Haar, F., Gerasimov, G., Tyler, V. Q., & Timmer, A. (2011). Universal salt iodization in the Central and Eastern Europe, Commonwealth of Independent States (CEE/CIS) Region during the decade 2000–09: Experiences,

123

Environ Geochem Health achievements, and lessons learned. Food and Nutrition Bulletin, 32(4 Suppl), S175–S294. Vanderpump, M. P., Lazarus, J. H., Smyth, P. P., Laurberg, P., Holder, R. L., Boelaert, K., et al. (2011). British thyroid association UK IodineSurvey Group: Iodine status of UK schoolgirls: a cross-sectional survey. Lancet, 377, 2007–2012. Vandevijvere, S., Amsalkhir, S., Mourri, A. B., VanOyen, H., & Moreno-Reyes, R. (2013). Iodine deficiency among Belgian pregnant women not fully corrected by iodine-containing multivitamins: A national cross-sectional survey. British Journal of Nutrition, 109, 2276–2284. Vandevijvere, S., Coucke, W., Vanderpas, J., Trumpff, C., Fauvart, M., Meulemans, A., et al. (2012). Neonatal thyroid-stimulating hormone concentrations in Belgium: A useful indicator for detecting mild iodine deficiency? PLoS ONE, 7, e47770. Velasco, I., Carreira, M., Santiago, P., et al. (2009). Effect of iodine prophylaxis during pregnancy on neurocognitive development of children during the first two years of life. Journal of Clinical Endocrinology and Metabolism, 94, 3234–3241. Vila, L., Serra-Prat, M., de Castro, A., Palomera, E., Casamitjana, R., Legaz, G., et al. (2011). Iodine nutritional status in pregnant women of two historically different iodine-deficient areas of Catalonia, Spain. Nutrition, 27, 1029–1033.

123

Vulsma, T., Gons, M. H., & De Vijlder, J. J. M. (1989). Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. New England Journal of Medicine, 321, 13–16. Whitehead, D. C. (1979). Iodine in the UK environment with particular reference to agriculture. Journal of Applied Ecology, 16, 269–279. Williams, G. R. (2008). Neurodevelopmental and neurophysiological actions of thyroid hormone. Journal of Neuroendocrinology, 20, 784–794. Wirth, E. K., Schweizer, U., & Ko¨hrle, J. (2014). Transport of thyroid hormone in brain. Frontiers in Endocrinology (Lausanne), 5, 98. Zimmermann, M. B., & Andersson, M. (2012a). Assessment of iodine nutrition in populations: Past, present, and future. Nutrition Reviews, 70, 553–570. Zimmermann, M. B., & Andersson, M. (2012b). Update on iodine status worldwide. Current opinion in Endocrinology, Diabetes, and Obesity, 19, 382–387. Zimmermann, M. B., Connolly, K., Bozo, M., Bridson, J., Rohner, F., & Grimci, L. (2006). Iodine supplementation improves cognition in iodine-deficient schoolchildren in Albania: A randomized controlled double blind study. The American Journal of Clinical Nutrition, 83, 108–114